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Arctigenin functions as a selective agonist of estrogen receptor β to restrict mTORC1 activation and consequent Th17

Xin Wu1,2, Bei Tong1, Yan Yang1

  • 1Department of Pharmacology of Chinese Materia Medica, China Pharmaceutical University, Tong Jia Xiang, Nanjing, China.

Oncotarget
|November 19, 2016
PubMed

Insights

Arctigenin inhibits Th17 cell differentiation and colitis by targeting estrogen receptor beta (ERβ). This interaction down-regulates mechanistic target of rapamycin complex 1 (mTORC1) activation, offering a potential therapeutic pathway.

Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Arctigenin previously inhibited Th17 cell differentiation and colitis via mechanistic target of rapamycin complex 1 (mTORC1) down-regulation.
  • The precise molecular mechanism underlying arctigenin's effects remained to be fully elucidated, particularly concerning its interaction with estrogen receptors (ERs).

Purpose of the Study:

  • To investigate the underlying mechanism of arctigenin's anti-colitis effects, focusing on its interaction with estrogen receptor beta (ERβ).
  • To determine if ERβ is the direct target of arctigenin mediating the inhibition of mTORC1 activation and Th17 cell differentiation.

Main Methods:

  • Utilized T cell lines and primary CD4+ T cells under Th17-polarization conditions.
  • Employed ERβ-specific antagonist (PHTPP) and siRNA to assess ERβ dependency.
  • Investigated arctigenin's binding affinity, complex dissociation, nuclear translocation, and phosphorylation of ERβ.
  • Analyzed the impact of ERβ activation on ERβ-raptor-mTOR complex assembly and mTORC1 activity.
  • Evaluated arctigenin's efficacy in a mouse model of colitis, with and without PHTPP treatment.

Main Results:

  • Arctigenin's inhibitory effect on mTORC1 activation was significantly diminished by ERβ antagonism or knockdown, indicating an ERβ-dependent mechanism.
  • Arctigenin acted as an ERβ agonist, promoting ERβ nuclear translocation, phosphorylation, and transcriptional activity.
  • ERβ activation by arctigenin led to mTORC1 inhibition through disruption of the ERβ-raptor-mTOR complex.
  • ERβ deficiency abolished arctigenin's inhibition of Th17 cell differentiation.
  • In vivo, ERβ activation and mTORC1 inhibition by arctigenin were abrogated by PHTPP in colitis mice.

Conclusions:

  • Estrogen receptor beta (ERβ) is identified as a key target protein for arctigenin.
  • Arctigenin inhibits mechanistic target of rapamycin complex 1 (mTORC1) activation via ERβ.
  • This ERβ-mediated inhibition of mTORC1 prevents Th17 cell differentiation and ameliorates colitis development.
Keywords:
Immune responseImmunityImmunology and Microbiology SectionTh17 cell differentiationarctigenincolitisestrogen receptor βmTORC1 activation

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